RESUMO
The Group IVA cytosolic phospholipase A(2) (GIVA PLA(2)) is a particularly attractive target for drug development because it is the rate-limiting provider of proinflammatory mediators. We previously reported the discovery of novel 2-oxoamides that inhibit GIVA PLA(2) [Kokotos, G.; et al. J. Med. Chem. 2002, 45, 2891-2893]. In the present work, we have further explored this class of inhibitors and found that the 2-oxoamide functionality is more potent when it contains a long 2-oxoacyl residue and a free carboxy group. Long-chain 2-oxoamides based on gamma-aminobutyric acid and gamma-norleucine are potent inhibitors of GIVA PLA(2). Such inhibitors act through a fast and reversible mode of inhibition in vitro, are able to block the production of arachidonic acid and prostaglandin E(2) in cells, and demonstrate potent in vivo anti-inflammatory and analgesic activity.
Assuntos
Amidas/síntese química , Anti-Inflamatórios não Esteroides/síntese química , Butiratos/síntese química , Caprilatos/síntese química , Ácidos Heptanoicos/síntese química , Fosfolipases A/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Aminobutiratos , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacologia , Butiratos/química , Butiratos/farmacologia , Caprilatos/química , Caprilatos/farmacologia , Linhagem Celular , Edema/tratamento farmacológico , Fosfolipases A2 do Grupo IV , Ácidos Heptanoicos/química , Ácidos Heptanoicos/farmacologia , Ativação de Macrófagos , Camundongos , Medição da Dor , Fosfolipases A/química , Fosfolipases A2 , Ratos , Ratos Endogâmicos F344 , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Novel inhibitors of human digestive lipases, lipophilic trifluoromethyl ketones, were developed. These analogues of the natural triacylglycerol substrates of lipases were designed to contain the carbonyl group of the trifluoromethyl ketone functionality in place of the carbonyl group of the scissile ester bond at the sn-1 position. The ester bond at the sn-3 position was replaced by an ether bond, while the secondary hydroxy group was either esterified or etherified. The inhibitors were prepared starting from solketal. The inhibition of human pancreatic and gastric lipases by the trifluoromethyl ketones was studied by the monolayer technique. 5,5,5-Trifluoro-1-(dodecyloxymethyl)-4-oxopentyl decanoate is the best synthetic inhibitor of human gastric lipase ever reported (inhibition constant alpha(50)=0.003).
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Cetonas/síntese química , Cetonas/farmacologia , Lipase/antagonistas & inibidores , Estômago/enzimologia , Indicadores e Reagentes , Cinética , Espectroscopia de Ressonância Magnética , Membranas Artificiais , Estômago/efeitos dos fármacos , Relação Estrutura-Atividade , Especificidade por Substrato , Triglicerídeos/metabolismoRESUMO
[reaction: see text] Novel inhibitors of human digestive lipases, aldehyde dialkyl and alkyl-acyl glycerol analogues, were developed. The inhibitors were prepared starting from 3-(benzyloxy)-1,2-propanediol. The inhibition of human pancreatic and gastric lipases by the aldehyde derivatives was studied using the monolayer technique. (1R)-1-[(Dodecyloxy)methyl]-4-oxobutyl decanoate caused a 50% decrease in HPL and HGL activities at 0.100 and 0.053 molar fractions, respectively.
Assuntos
Aldeídos/síntese química , Aldeídos/farmacologia , Sistema Digestório/enzimologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Lipase/antagonistas & inibidores , HumanosRESUMO
A novel class of potent human cytosolic phospholipase A(2) (GIVA PLA(2)) inhibitors was developed. These inhibitors were designed to contain the 2-oxoamide functionality and a free carboxyl group. Among the compounds tested, a long-chain 2-oxoamide containing L-gamma-norleucine was the most potent inhibitor, causing a 50% decrease in GIVA PLA(2) activity at 0.009 mole fraction.
